Highly reliable ingestible event markers and methods for using the same

ABSTRACT

Ingestible event markers having high reliability are provided. Aspects of the ingestible event markers include a support, a control circuit, a first electrochemical material, a second electrochemical material and a membrane. In addition, the ingestible event markers may include one or more components that impart high reliability to the ingestible event marker. Further, the ingestible event markers may include an active agent. In some aspects, the active agent, such as a pharmaceutically active agent or a diagnostic agent may be associated with the membrane.

CROSS-REFERENCE TO RELATED APPLICATIONS

Pursuant to 35 U.S.C. § 119 (e), this application claims priority to thefiling date of U.S. Provisional Patent Application Ser. No. 61/173,511filed Apr. 28, 2009 and to the filing date of U.S. Provisional PatentApplication Ser. No. 61/173,564 filed Apr. 28, 2009; the disclosure ofwhich applications are herein incorporated by reference.

INTRODUCTION

There are many instances in both medical and non-medical applicationswhere one desires to note a personal event, i.e., an event that isspecific to a given individual. Examples of medical applications whereone may wish to note an event that is specific to a given individualinclude, but are not limited to, the onset of one or more physiologicalparameters of interest, including disease symptoms, the administrationof a medication, etc. Examples of non-medical applications where onedesires to note an event that is specific to a given individual include,but are not limited to: the ingestion of certain types of foods, e.g.,for individuals on controlled diets, the commencement of an exerciseregimen, etc.

Because there are many instances where one wishes to note a personalevent, a variety of different methods and technologies have beendeveloped to make such notation possible. For example, log books andtechniques have been developed in which individuals, e.g., patientsand/or their health care provides, can record, e.g., by manually writingor data entry, time and date of an event.

However, there continues to be a need for improvements in personal eventmonitoring. For example, manually logging when an event takes place canbe time consuming and prone to error.

SUMMARY

Event markers, e.g., ingestible event markers, having high reliabilityare provided. Aspects of the event markers include a support, a controlcircuit physically associated with the support to control the highlyreliable event marker, a first electrochemical material physicallyassociated with the support and electrically coupled to the controlcircuit, a second electrochemical material electrically coupled to thecontrol circuit and physically associated with the support at a locationdifferent from the location of the first material, such that the firstand second electrochemical materials are electrically isolated from eachother; and a membrane physically associated to the support andpositioned relative to the first electrochemical and secondelectrochemical materials to generate a virtual dipole length largerthan an actual dipole length defined by the first and the secondelectrochemical materials.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A to 1F provide views of various IEM configurations according todifferent aspects of the invention.

FIGS. 2A and 2B provide illustrations of an IEM that includes a membranehaving deployable arms.

FIG. 3 provides a view of an IEM in which the IEM component ispositioned off-center relative to the membrane.

FIG. 4 provides a view of an IEM having a weight positioned on one sideof the membrane.

FIG. 5 provides a view of an IEM having a water-swellable componentpositioned on side of the membrane.

FIGS. 6A and 6B provide views of different IEM configurations whichincorporate effervescent structures.

FIGS. 7A, 7B and 8 provide different views IEMs having a tabletconfiguration.

DETAILED DESCRIPTION

Event markers, e.g., ingestible event markers (“IEMs”, sometimesreferred to herein as “identifiers”), having high reliability areprovided. Aspects of the ingestible event markers include a support, acontrol circuit physically associated with the support to control thehighly reliable event marker, a first electrochemical materialphysically associated with the support and electrically coupled to thecontrol circuit, a second electrochemical material electrically coupledto the control circuit and physically associated with the support at alocation different from the location of the first material, such thatthe first and second electrochemical materials are electrically isolatedfrom each other; and a membrane physically associated to the support andpositioned relative to the first electrochemical and secondelectrochemical materials to generate a virtual dipole length largerthan an actual dipole length defined by the first and the secondelectrochemical materials.

Ingestible Event Markers

As summarized above, ingestible event markers (IEMs) of the inventionare highly reliable. By “highly reliable” is meant that the ingestibleevent markers of the invention correctly generate and transmit a signalwhen employed in an application for which they are intended at afrequency of 80% or greater, such as 90% or greater, including 95% orgreater. Highly reliable ingestible event markers of the invention maycorrectly generate and transmit a signal at a frequency of 99.5% orgreater, such as 99.9% or greater, and in some instances correctlygenerate and transmit a signal at a frequency of 100%. As furtherdeveloped below, the highly reliable characteristic of the ingestibleevent markers may arise from one or more components and/or structuralfeatures of the IEM, as described in greater detail below. As reviewedin greater detail below, one or more components and/or structuralfeatures of the IEM may impart to the IEM one or more of the followingcharacteristics: enhanced signal strength, extended lifetime, enhancedwetting by stomach fluid, reduced propensity for blockage by GI lining,reduced propensity of blockage by bubbles and/or anti-foaming, reducedpropensity for floating, as compared to a suitable control. Thesedesirable characteristics may be imparted to a given IEM by one or morestructural features and/or chemical constituents, as reviewed in greaterdetail below.

An ingestible event marker is a device that is dimensioned to beingestible and includes an IEM made up of an IEM circuitry component anda membrane. The IEM may also include a vehicle. A pharmaceuticallyactive agent may be present in the membrane and/or vehicle. As the IEMsare dimensioned to be ingestible, in certain instances they are sized sothat they can be placed in a human mouth and swallowed. In someinstances, IEMs of the invention have a longest dimension that is 30 mmor less, such as 20 mm or less, including 5 mm or less.

Various aspects of event markers, e.g., ingestible event markers, ofinterest are described in PCT application serial no. PCT/US2006/016370published as WO/2006/116718; PCT application serial no.PCT/US2007/082563 published as WO/2008/052136; PCT application serialno. PCT/US2007/024225 published as WO/2008/063626; PCT applicationserial no. PCT/US2007/022257 published as WO/2008/066617; PCTapplication serial no. PCT/US2008/052845 published as WO/2008/095183;PCT application serial no. PCT/US2008/053999 published asWO/2008/101107; PCT application serial no. PCT/US2008/056296 publishedas WO/2008/112577; PCT application serial no. PCT/US2008/056299published as WO/2008/112578; and PCT application serial no.PCT/US2008/077753 published as WO2009/042812; the disclosures of whichare herein incorporated by reference. In certain aspects, the ingestibleevent markers are disrupted upon administration to a subject. As such,in certain aspects, the compositions are physically broken, e.g.,dissolved, degraded, eroded, etc., following delivery to a body, e.g.,via ingestion, injection, etc. The compositions of these aspects aredistinguished from devices that are configured to be ingested andsurvive transit through the gastrointestinal tract substantially, if notcompletely, intact.

Highly Reliable Event Marker

In various aspects, the highly reliable event marker includes a support,a control circuit physically associated with the support to control thehighly reliable event marker, a first electrochemical materialphysically associated with the support and electrically coupled to thecontrol circuit, a second electrochemical material electrically coupledto the control circuit and physically associated with the support at alocation different from the location of the first material, such thatthe first and second electrochemical materials are electrically isolatedfrom each other; and a membrane physically associated to the support andpositioned relative to the first electrochemical and secondelectrochemical materials to generate a virtual dipole length largerthan an actual dipole length defined by the first and the secondelectrochemical materials.

The highly reliable event marker may be configured to be activated uponcontact with fluid at the target site, such as a conducting fluid, e.g.,a stomach fluid, providing, for example, a voltage potential difference.In various aspects, the control circuit controls the conductance throughlogic that alters the overall impedance of the system. The controlcircuit, for example, may be electrically coupled to a clock. The clockmay provide a clock cycle to the control circuit. Based upon theprogrammed characteristics of the control circuit, when a set number ofclock cycles have passed, the control circuit alters the conductancecharacteristics between electrochemical materials. This cycle may berepeated and thereby the control circuit may produce a unique currentsignature characteristic, sometimes referred to herein as a “currentsignature”. The control circuit may also be electrically coupled to amemory. Both the clock and the memory may be powered by the voltagepotential created between the materials when in contact with aconducting fluid.

With respect to current signatures, the current signatures maydistinguish one class of highly reliable event marker from other typesor may be universally unique, such as where the current signature isanalogous to a human fingerprint which is distinct from any otherfingerprint of any other individual and therefore uniquely identifies anindividual on a universal level. In various aspects, the control circuitmay generate a variety of different types of communications, includingbut not limited to: RF signals, magnetic signals, conductive (nearfield) signals, acoustic signals, etc.

Receivers, as heretofore described in various aspects of the presentinvention, do not require any additional cable or hard wire connectionbetween the device and a receiver of the communication, sometimesreferred to herein as a detector.

In some instances, the highly reliable event marker includes twodissimilar electrochemical materials which serve as a cathode and ananode. When the two dissimilar electrochemical materials come in contactwith the body fluid, such as stomach fluid, a potential difference(voltage) is generated between the cathode and the anode as a result ofthe respective oxidation and reduction reactions occurring at the twodissimilar electrochemical materials. The dissimilar electrochemicalmaterials making up the electrochemical materials can be made of any twomaterials appropriate to the environment in which the IEM circuitrycomponent will be operating. The active materials are any pair ofmaterials with different electrochemical potentials. The electrochemicalmaterial materials may be chosen to provide for a voltage upon contactwith the target physiological site that is sufficient to drive a signalgeneration element of the IEM circuitry component. Where desired, thevoltage provided by the two dissimilar electrochemical materials uponcontact of the metals of the power source with the target physiologicalsite is 0.001 V or higher, including 0.01 V or higher, such as 0.1 V orhigher, e.g., 0.3 V or higher, including 0.5 volts or higher, andincluding 1.0 volts or higher, where in certain aspects, the voltageranges from about 0.001 to about 10 volts, such as from about 0.01 toabout 10 V.

Anode materials of interest include, but are not limited to: magnesium,zinc, sodium, lithium, iron and alloys thereof, e.g., Al and Zn alloysof Mg, which may or may not be intercalated with a variety of materialssuch, as graphite with Li, K, Ca, Na, Mg, and the like. Cathodematerials of interest include, but are not limited to, copper salts,such as copper salts of iodide, chloride, bromide, sulfate, formate,Fe³⁺ salts, e.g., orthophosphate, pyrophosphate, etc. One or both of themetals may be doped with a non-metal, for example to enhance the voltageoutput of a partial power source or a battery. Non-metals that may beused as doping agents in certain aspects include, but are not limitedto: sulfur, iodine and the like. In certain aspects, the electrochemicalmaterial materials are cuprous iodine (CuI) or cuprous chloride (CuCl)as the anode and magnesium (Mg) metal or magnesium alloy as the cathode.Aspects of the present invention use electrochemical material materialsthat are not harmful to the human body. When the materials are exposedand come into contact with the body fluid, such as stomach acid or othertypes of fluid (either alone or in combination with a dried conductivemedium precursor), a potential difference, that is, a voltage, isgenerated between the electrochemical materials as a result of therespective oxidation and reduction reactions incurred to the twoelectrochemical material materials. A voltaic cell, or battery, canthereby be produced. Accordingly, in embodiments of the invention, suchpower supplies are configured such that when the two dissimilarmaterials are exposed to the target site, e.g., the stomach, thedigestive tract, etc., a voltage is generated.

Electrochemical material materials of interest include those thatgenerate substantially little, if any, gaseous bubbles upon contact withan aqueous physiological fluid, such as stomach acid. Electrochemicalmaterial materials of interest include metal alloys, where alloys ofinterest include, but are not limited to, alloys of Mg, Zn, Al, and Li.When present, the amount of metal alloy may range from 0.01 to 15, suchas 0.1 to 15 including 1 to 15% by weight. One or more different alloyelements may be present in the alloy. Of interest in some aspects are“bubble-free” Mg alloys which are MgAl or MgZn alloys, such as but notlimited to: AZ31 magnesium alloy, AZ61 magnesium alloy, and the like.

Highly reliable event markers, e.g., IEMs, may include a solid support.In certain aspects, the solid support is small, e.g., where it isdimensioned to have a width ranging from about 0.01 mm to about 20 mm,e.g., from about 0.1 mm to about 10 mm, including from about 0.5 mm toabout 2 mm; a length ranging from about 0.01 mm to about 20 mm, e.g.,from about 0.1 mm to about 20 mm, including from about 0.5 mm to about 2mm, and a height ranging from about 0.01 mm to about 10 mm, e.g., fromabout 0.05 mm to about 2 mm, including from about 0.1 mm to about 0.5mm. The solid support element may take a variety of differentconfigurations, such as but not limited to: a chip configuration, acylinder configuration, a spherical configuration, a disc configuration,etc, where a particular configuration may be selected based on intendedapplication, method of manufacture, etc. While the material from whichthe solid support is fabricated may vary considerably, in certainaspects the solid support is made up of a semiconductor material, e.g.,silicon.

The phrase “single integrated circuit” refers to a single circuitstructure that includes all of the different desired functional blocksfor the device. In these aspects, the integrated circuit is a monolithicintegrated circuit (also known as IC, microcircuit, microchip, siliconchip, computer chip or chip) that is a miniaturized electronic circuit(which may include semiconductor devices, as well as passive components)that has been manufactured in the surface of a thin substrate ofsemiconductor material. The integrated circuits of certain aspects ofthe present invention may be hybrid integrated circuits, which areminiaturized electronic circuits constructed of individual semiconductordevices, as well as passive components, bonded to a substrate or circuitboard.

IEMs may be fabricated using any convenient protocol. IEM fabricationprotocols of interest include, but are not limited to, those describedin PCT application serial no. PCT/US2006/016370 published asWO/2006/116718; PCT application serial no. PCT/US2007/082563 publishedas WO/2008/052136; PCT application serial no. PCT/US2007/024225published as WO/2008/063626; PCT application serial no.PCT/US2007/022257 published as WO/2008/066617; PCT application serialno. PCT/US2008/052845 published as WO/2008/095183; PCT applicationserial no. PCT/US2008/053999 published as WO/2008/101107; PCTapplication serial no. PCT/US2008/056296 published as WO/2008/112577;PCT application serial no. PCT/US2008/056299 published asWO/2008/112578; and PCT application serial no. PCT/US2008/077753, thedisclosures of which are herein incorporated by reference.

A given IEM may include a single IEM, or two or more IEMs, such as threeor more, four or more, five or more, six or more, seven or more, eightor more, nine or more, or ten or more IEMs.

In some instances, an IEM may include a swellable or water-absorbingcoating that serves to control the microenvironment of the IEM in adesired manner. Of interest in certain instances as swellable coatingsare hydrogel coatings. Hydrogel coatings are polymeric coatings made upof one or more different types of non-water soluble polymers, where thecoatings absorb water upon contact with an aqueous medium to produce ahydrated gel-structure that has a high water content, such as 90% ormore w/w, including 95% or more w/w, such as 99% or more w/w. Anyphysiologically acceptable hydrogel composition may be employed as acoating, where hydrogel compositions of interest may include one or moreof the following polymers: polyethylene oxides, acetates, etc. In someinstances, the hydrogel coating may include one or more agents whichprovide for a controlled environment (for example in terms ofconductivity or pH) when the ingestible event marker reaches the targetphysiological site. Agents of interest include, but are not limited to:salts of physiologically acceptable electrolytes, such as but notlimited to: sodium ion, chloride ion, potassium ion and calcium ion,magnesium ion, etc. Specific physiologically compatible salts ofinterest include, but are not limited to: KCl, NaCl, MgCl₂, and thelike. Desired pH may range from 1 to 8, such as 2 to 7, and may beimparted by the presence of any suitable buffering agent.

Coatings may take a variety of different configurations, such as layers,snap-fit pre-made capsule components, etc. When present, coatings maycover only a portion of the ingestible event marker envelope the entiredevice. The coating may be uniform in terms of thickness.

Membrane

IEMs may include at least a pair of signal transmission elements, e.g.,in the form of first and second electrochemical materials, which have anactual dipole length. Also present is a membrane which, for example,produces a virtual dipole length between the pair of transmissionelements that is larger than the actual dipole length. In addition tocontrolling the magnitude of the current path between the materials, amembrane (sometimes referred to herein as “amplifier”) is used toincrease the “length” of the current path and, hence, act to boost theconductance path, as disclosed in the U.S. patent application Ser. No.12/238,345 entitled, “In-Body Device with Virtual Dipole SignalAmplification” filed Sep. 25, 2008, and in the U.S. patent applicationSer. No. 12/564,017 entitled, “Communication System with Partial PowerSource” filed Sep. 21, 2009 the entire content of which are incorporatedherein by reference. Alternatively, throughout the disclosure herein,the terms “membrane”, and “amplifier” are interchangeably with the term“current path extender” without impacting the scope or the presentaspects and the claims herein. While the length of the virtual dipoleprovided by the membrane may vary, in certain instances the length ofthe virtual dipole is two or more times, such as three or more times,e.g., five or more times, twenty or more times, etc., longer than thelength of the actual dipole that exists between the pair of transmissionelements. As the length of an actual dipole in a given IEM may vary,ranging in certain instances from 100 μm to 2 cm, such as 300 μm to 1mm, the length of the virtual dipole may range, in certain instances,from 200 μm to 20 cm, such as 600 μm to 20 mm. In addition to the IEMsof the invention further include a membrane, where the membrane includesa pharmaceutically active agent.

The membrane may have a variety of different configurations, so long asit serves to provide a virtual dipole having a length that is longerthan that of the actual dipole length between two or more of, such as apair of, of signal transmission elements. In certain aspects, themembrane is a structure that is positioned between the pair of signaltransmission elements. The membrane may have a two-dimensional or three-dimensional configuration, and may have any convenient shape, such assquare, disc, triangular, ovoid, irregular, etc., as developed ingreater detail below. The length of the virtual dipole provided by thesignal amplification element is, in certain instances, dependent on theparticular shape of the signal amplification element. For example, wherethe signal amplification element has a disc configuration, as developedin greater detail below, the length of the virtual dipole issubstantially the same as, if not identical to, the radius of the disc.

The pair of transmission elements are, in certain instances, a pair ofelectrochemical materials positioned on opposing sides of a solidsupport, e.g., where the solid support comprises an integrated circuit.For example, where the integrated circuit has an upper electrochemicalmaterial and lower electrochemical material on opposing sides orsurfaces of an integrated circuit, the membrane may be an insulativematerial (or composite material) positioned between the upper and lowerelectrochemical materials. The outer edge of the membrane may or may notextend beyond the edge of the electrochemical materials, where examplesof these differing aspects are reviewed in greater detail below.

FIG. 1A to provides a view of an aspect of an IEM according to theinvention which has a membrane that extends beyond the outer edges ofthe membranes to provide a virtual dipole having a length that is longerthan the actual dipole between the membrane. As shown in FIG. 1A, IEM 10includes integrated circuit 2, having an upper electrochemical material4 (which may comprise two distinct material layers) and a lowerelectrochemical material 6. Also shown is disc shaped membrane 8. FIG.1B provides an overhead view of the IEM shown in FIG. 1A, depicting thedisc shape of upper electrochemical material 4 and the positioning ofthe upper electrochemical material in the center of disc shaped membrane8. The distance that the edge of the membrane may extend beyond the edgeof electrochemical materials may vary, and in certain aspects is 0.05 mmor more, e.g., 0.1 mm or more, including 1.0 mm or more, such as 5.0 mmor more and including 10 mm or more, where the distance may not exceed100 mm in certain aspects.

As can be seen in the aspect depicted in FIGS. 1A to 1B, the upper andlower electrochemical materials are planar electrochemical materials,where these electrochemical materials may have any convenient shape,e.g., square, disc, etc. The disc shaped membrane or amplifier 18 is aplanar disc structure, where the edge of the membrane extends beyond theedge of the planar upper and lower electrochemical materials. In thedepicted aspect, the radius of the membrane is longer than the radius ofthe upper and lower electrochemical materials, e.g., by 1 mm or more,such as by 10 mm or more.

Membranes may have “two-dimensional” or “three-dimensional”configurations. Membrane configurations of interest are furtherdescribed in PCT application serial no. US2008/077753 published asWO2009/042812, as well as U.S. provisional application Ser. nos.61/142,849 and 61/173,511; the disclosures of which are hereinincorporated by reference. In some instances, IEMs of the inventioninclude a membrane having a configuration that is chosen to provide forreduced susceptibility to signal-compromising events following contactwith the target physiological site. One type of signal-compromisingevent that may occur is where the IEM adheres to a wall of thegastro-intestinal (GI) tract, such as the stomach wall, and thereby isprevented from interacting freely with fluid at the target physiologicalsite. The membrane may be configured in a three-dimensional shape whichdiscourages adhesion to a GI tract wall. One such configuration is shownin FIGS. 10 and 10. FIG. 10 provides a cross-sectional view of an IEM 10that includes an IEM circuitry component 12 and a membrane 14 that hasopposing curved edges 16 and 18. FIGS. 1E and 1F provide views ofadditional types of membranes having a three-dimensional shape thatdiscourages adherence to a GI tract wall. In FIG. 1E, IEM 10 includesIEM circuitry component 12 centrally positioned in membrane 14. Membrane14 includes projections 15 which prevent the bottom side of the IEMcircuitry component 12 from lying flat on a GI tract wall. In FIG. 1F,IEM 10 includes IEM circuitry component 12 centrally positioned onmembrane 14, where membrane 14 has a concave configuration whichprevents the bottom side of the IEM circuitry component from lying flaton a GI tract wall.

Alternatively, the membrane may include one or more deployable elementswhich serve to prevent the IEM from adhering to a GI tract wall. Anexample of such an IEM is shown in FIG. 2A, which depicts IEM 20 havingIEM circuitry component 22 and membrane24. Also shown in FIG. 2A aredeployable elements 26 and 28 having opposing configurations. As theseelements are deployable, they are present in a first configuration priorto IEM ingestion and then deploy to a second position followingingestion. A deployable configuration is depicted in FIG. 2B, where IEM20 of FIG. 2A is shown with the end 27 of arm 26 associated with thesurface of the membrane 24, for example with a physiologicallyacceptable glue 25 that dissolves upon contact with an aqueous fluid.With respect to the IEM shown in FIG. 2B, upon contact with a targetphysiological fluid, such as stomach fluid, the glue dissolves to deploythe arms, such that the IEM assumes the configuration shown in FIG. 2A.

In yet another configuration of interest, the IEM circuitry component isnon-centrically positioned relative to the membrane. An example of suchan IEM is shown in FIG. 3, where IEM 30 includes IEM circuitry component32 non-centrically positioned in the membrane 34.

Where desired, one or more components which promote movement of the IEMin a liquid environment, such as when present in stomach fluid, may beassociated with the membrane. For example, an IEM may have a weightnon-centrically associated with a membrane. An example of such aconfiguration is shown in FIG. 4. In FIG. 4, IEM 40 includes IEMcircuitry component 42 and membrane 44. Also shown is weight 46 which isnon-centrically associated with the membrane. Upon contact with a fluid,the weight serves to move the IEM in the direction of the arrow so thatthe IEM sinks into and becomes immersed in the fluid. In the aspectshown in FIG. 4, the weight has a density greater than that of stomachfluid and serves to pull the edge of the IEM with which the weight isassociated down relative the opposite edge of the IEM. Instead of aweight, the IEM may have a swellable component non-centricallypositioned on the membrane which, upon contact with an aqueous fluid,swells in a manner such that its density decreases relative to stomachfluid and it lifts one edge of the IEM relative to the opposing edge. Anexample of such an IEM is shown in FIG. 5, wherein IEM 50 includes IEMcircuitry component 52 and -membrane 54, as well as water-swellablecomponent 56. Water-swellable component 56 swells under aqueousconditions to lift one edge of the IEM relative to the opposite edge, asindicated by the arrow.

To enhance movement of the IEM when present in a liquid environment,such as a target physiological fluid, effervescent structures thatgenerate bubbles upon contact with the target physiological fluid may beassociated with one or more locations of the membrane. One or moredistinct effervescent structures may be associated with the membrane. Ofinterest are membranes that include two distinct effervescent structuresassociated with opposing sides of the membrane, such that a firsteffervescent structure is present on a first side of the membrane and asecond effervescent structure is present on a second side of themembrane. In this orientation, the effervescent structures, upongeneration of bubbles, force the IEM to rotate in a liquid environmentas a result of opposing forces applied to the edges of the membrane.Representations of IEMs that include effervescent structures are shownin FIGS. 6A and 6B. FIG. 6A shows an IEM 60 having IEM circuitrycomponent 62 that is centrically positioned in membrane 64. Also shownare effervescent structures 66 and 68 which generate bubbles uponcontact with a physiological fluid, as shown. The bubbles apply opposingforces to the edges of the membrane, causing the IEM to rotate asindicated by the arrows. In FIG. 6B, IEM 63 is analogous to IEM 60 ofFIG. 6A, with the exception that the membrane has curved edges 65 and67. The effervescent structure may include any convenient effervescentmaterial that is physiologically acceptable and generates gas bubblesupon contact with an aqueous fluid, such as stomach fluid. Theeffervescent material may generate a variety of gasses, such as carbondioxide, hydrogen, oxygen, and the like. Of interest in some instancesare effervescent materials that include magnesium, which generateshydrogen gas upon contact with an aqueous physiological fluid. Othereffervescent materials of interest include acid sources, such as but notlimited to food acids, acid and hydrite antacids such as, for example,citric, tartaric, amalic, fumeric, adipic, and succinic acids. Carbonatesources of interest include, but are not limited to, dry solid carbonateand bicarbonate salt such as, sodium bicarbonate, sodium carbonate,potassium bicarbonate and potassium carbonate, magnesium carbonate andthe like.

The membrane may be fabricated from a number of different materials,where the membrane may be made of a single material or be a composite oftwo or more different types of materials. In choosing a suitablematerial or materials, one characteristic of interest is mechanicalstrength. As indicated above, the membrane material may be a compositestructure of two or more materials, e.g., an insulative materialdeposited on a metallic layer.

In certain instances, the membrane will have a mechanical strengthsufficient to withstand the mechanical forces typical of thegastrointestinal (GI) tract without folding onto itself and losing itsshape. This desired mechanical strength may be chosen to last for atleast the duration of the communication, which may be 1 second orlonger, such as at least 1 minute or longer, up to 6 hours or longer. Incertain aspects, the desired mechanical strength is selected to leastfor a period of time ranging from 1 to 30 minutes. The desiredmechanical strength can be achieved by proper selection of polymer orfillers, or mechanical design (e.g., lamination of multiple layers, orcurvature of the amplifier surface) to increase the mechanical strengthof the final structure.

Membranes of the invention are ones that are electrically insulating. Assuch, the materials from which the membranes are fabricated areelectrically insulating materials. A given material is electricallyinsulating if it has a resistivity that is 2 times or greater than themedium in which the device operates (e.g., stomach fluid), such as 10times or greater, including 100 times or greater than the medium inwhich the device operates.

Additional characteristics of interest for the membranes includeingestibility and low risk of blockage. It is desirable that themembrane be made of safe and ingestible material, such as food additivesor pharmaceutical excipients. It may be further desirable to make themembrane in such a way to ensure low risk for blockage of the GI tractby one or more devices. This can be achieved via chemical or physicaldissolution or digestion of the amplifier material, or mechanicalbreakdown of the membrane, or a combination of the two. For example, themembrane can contain one or more materials that chemically or physicallydissolve in GI fluids after a certain amount of time. The material canalso be selected to become soluble upon reaching certain parts of the GItract where the chemical environment is different, for example, a changein pH (e.g., from pH 1-2 in stomach to pH>5 in intestine) or enzymaticcomponents (such as enzymes present in the colon). The membrane may alsobe mechanically designed to have a weak point that dissolves and allowsthe entire structure to break up. The membrane may be constituted ofseveral layers, for example an inner soluble or swelling layer and anouter layer that controls the dissolution rate of the inner layer; aftera certain amount of time, the inner layer dissolves or swells, burstingapart the entire structure. The membrane does not need to be fullysoluble or digestible to eliminate the risk of blockage; it issufficient that the membrane becomes mechanically pliable or friableenough that it folds or breaks up under modest mechanical strain in theGI tract.

In certain aspects, the membrane may also serve as a reservoir of activepharmaceutical agents. The membrane will then serve the dual purpose ofincrease the dipole and serving as a drug depot. As summarized above,membranes of interest include an amount of a pharmaceutically activeagent. The phrase “pharmaceutically active agent” (also referred toherein as drugs) refers to a compound or mixture of compounds whichproduces a physiological result, e.g., a beneficial or useful result,upon contact with a living organism, e.g., a mammal, such as a human.Pharmaceutically active agents are distinguishable from such componentsas excipients, carriers, diluents, lubricants, binders and otherformulating aids, and encapsulating or otherwise protective components.The pharmaceutically active agent may be any molecule, as well asbinding portion or fragment thereof, that is capable of modulating abiological process in a living subject. In certain aspects, thepharmaceutically active agent may be a substance used in the diagnosis,treatment, or prevention of a disease or as a component of a medication.In certain aspects, the pharmaceutically active agent may be a chemicalsubstance, such as a narcotic or hallucinogen, which affects the centralnervous system and causes changes in behavior.

The amount of pharmaceutically active agent that is present in themembrane may vary. In some instances, the amount of pharmaceuticallyactive agent that is present in the membrane may range from 0.01 to 100%by weight. Specific pharmaceutically active agents of interest include,but are not limited to, those described and listed below.

Depending on the particular configuration of a membrane, the dispositionof the pharmaceutically active agent in the membrane may vary. Forexample, the active agent may be homogeneously dispersed in themembrane. Alternatively, the active agent may be confined to aparticular location or locations within the membrane, so that themembrane includes regions that have pharmaceutically active agent andregions that do not. An example of such a membrane is a membrane that isporous, where the pores of the membrane are filled with apharmaceutically active agent. In such aspects, the porosity may rangefrom 5 to 75% or more after swelling.

In some instances, the membrane is configured to provide for controlledrelease of the pharmaceutically active agent that is present in themembrane. By “controlled release” is meant that the membrane isconfigured such that the pharmaceutically active agent is released fromthe membrane upon contact with the target physiological site in apredetermined manner. In other words, pharmaceutically active agent isreleased from the membrane (upon contact with the target physiologicalsite” in a way that has been predetermined, such as over an extendedperiod of time, etc. As such, the pharmaceutically active agent isreleased from the membrane at predetermined intervals or gradually overa period of time.

The membrane can be configured to provide for controlled release of thepharmaceutically active agent using a variety of different approaches.For example, where the membrane is a homogenous structure, signalcomponents or ingredients of the membrane may be chosen to provide forcontrolled release of the pharmaceutically active agent therefrom.Alternatively, where the membrane is porous, the porosity can be chosento impart the desired controlled release characteristics to themembrane.

In yet other instances, one or more coating layers may be employed toimpart controlled release characteristics to the membrane. In someinstances, the release profile of the active agent from the membrane iscontrolled by a single coating applied to the membrane. In yet otheraspects, a membrane may include two or more distinct coatings. In yetother instances, the coating layers may be fabricated from partly orentirely soluble polymer matrix materials which provide for a desiredcontrolled release profile. Coatings of interest include those describedin greater detail below.

In certain instances, the membrane has a multilayer configuration.Multilayered membrane configurations may be configured in a number ofdifferent ways. In some aspects, two or more of the different layers ofthe multilayered membrane may include the same active agent, where themultilayered configuration (for example where the two different layershave different compositions) provides for a desired controlled releaseprofile of the active agent. In such aspects, the amount of active agentin each active agent comprising layer may be the same or different. Inyet other aspects, two or more of the layers of a multilayered membranemay include different active agents.

Where desired, each layer of the multilayered membrane may include anIEM. In such instances, a given IEM will have a multilayered membranewhere a distinct IEM is present in two or more layers of themultilayered membrane.

Where desired, the membrane may be configured such that the release ofthe active agent from the membrane is coupled to the activation of theevent marker so that the IEM activation and communication coincides withactive agent release, such as the precise start of the release of theactive agent from the membrane.

As developed in further detail below, other components of the IEM may beconfigured to impart a controlled release profile to the active agentassociated with the membrane, where these other components may bepresent instead of or in combination with membrane controlled releasecomponents, such as described above. For example, where the IEM includesa vehicle, such as a tablet or capsule, the vehicle may be configured tocontrol release of the active agent from the membrane.

The membrane may be fabricated from various materials, categories ofmaterials, and/or combinations of materials. Material categories ofinterest include, for example, but are not limited to: matrix materials;filler materials; soluble disintegrant materials; plasticizing agents;coatings; and wetting agents.

The surface of the membrane may also contain an anti-adhesion layer thatprevents a transmitter from adhering to the stomach lining or gettingblocked by objects in the GI tract such as food residue. Ananti-adhesion film may also be used to prevent two or more devices fromadhering to each other and blocking each other's communication.

In various aspects, the membrane may be fabricated from variousmaterials, categories of materials, and/or combinations of materials.The categories include, for example, but are not limited to: filmforming or binding/adhesive agents; fillers; soluble materials ordisintegrants; plasticizing agents; coatings; and wetting agents.

The film forming or binding/adhesive agents include, for example, butare not limited to: agar; carageenan; cellulose acetate; chitosan;copovidone; ethyl cellulose; gelatin; gums (e.g., acacia, xanthan, guar,etc.); sugars (e.g., lactose, mannitol, xylitol, etc.); hydrogels (e.g.,hydroxethyl cellulose, sodium alginate, urethane, etc.); acrylic acidpolymers, cellulose acetate, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose,carboxymethylcellulose, ethylcellulose, methacrylic acid copolymer,methyl hydroxyethylcellulose, polyethylene glycol, polyvinyl acetatephthalate, polyvinyl alcohol, povidone, starch, carbomers, dextrin,hypromellose, poly(methylvinyl ether/maleic anhydride), chitosan,glyceryl monooleate, polyethylene oxide, polycarbophil, acacia,ceretonia, confectioner's sugar, cottonseed oil, dextrates, dextrose,glyceryl behenate, hydrogenated vegetable oil, hydroxypropyl starch,inulin, lactose, glucose, magnesium aluminum silicate, maltodextrin,maltose, methylcellulose, poloxamer, polycarbophil, polydextrose,polymethacrylates, stearic acid, sucrose, sunflower oil, zein, aluminumstearate, calcium silicate, colloidal silicon dioxide, glycerylpalmitostearate, pectin, polyethylene alkyl ethers, propylene carbonate,sodium ascorbate, zinc acetate, urethane, ammonium alginate,chlorpheniramine maleate, dibutyl phthalate, dibutyl sebacate, diethylphthalate, dimethyl phthalate, ethyl lactate, vanillin, shellac, and thelike.

The fillers include, for example, but are not limited to: oxides, e.g.,titanium dioxide, magnesium oxide, etc.; silicates, e.g., magnesiumsilicate; phosphates, e.g., dicalcium phosphate; carbonates andbicarbonates; starches; cellulosic materials, e.g., microcrystallinecellulose; acacia, agar, alginic acid, carbomers,carboxymethylcellulose, carrageenan, cellulose acetate phthalate,ceratonia, chitosan, confectioner's sugar, copovidone, cottonseed oil,dextrates, dextrin, dextrose, ethylcellulose, gelatin, glycerylbehenate, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose,hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylstarch, hypromellose, inulin, lactose, glucose, magnesium aluminumsilicate, maltodextrin, maltose, methylcellulose, microcrystallinecellulose, poloxamer, polycarbophil, polydextrose, polyethylene oxide,polymethacrylates, povidone, sodium alginate, starch, stearic acid,sucrose, sunflower oil, zein, bentonite, calcium stearate, carbomers,cellulose, colloidal silicon dioxide, kaolin, maltitol, sesame oil,sodium starch glycolate, sorbitan esters, tragacanth, xanthan gum,mannitol, ammonium alginate, calcium carbonate, calcium phosphate,calcium sulfate, cellulose, cellulose acetate, erythritol, fructose,fumaric acid, glyceryl palmitostearate, isomalt, kaolin, lactitol,magnesium carbonate, magnesium oxide, mannitol, simethicone, trehalose,xylitol, and the like.

The soluble materials or disintegrants include, for example, but are notlimited to: alginates (e.g., sodium or calcium); crosscarmellose sodium,carbpoxymethyl cellulose sodium, crospovidone, hydroxypropyl, cellulose,hydroxypropyl methyl cellulose, hypromellose, lactose mannitol,polyvinyl alcohol, and salts such as sodium or potassium chloride,alginic acid, calcium alginate, carboxymethylcellulose, cellulose,chitosan, colloidal silicon dioxide, croscarmellose sodium,crospovidone, docusate sodium, guar gum, hydroxypropyl cellulose,magnesium aluminum silicate, methylcellulose, microcrystallinecellulose, polacrilin potassium, povidone, sodium alginate, sodiumstarch glycolate, starch, and the like.

The plasticizing agents include, for example, but are not limited todibutyl sebacate, triethyl citrate, andtriacetin, acetyltributylcitrate, acetyltriethyl citrate, benzyl benzoate, cellulose acetatephthalate, chlorbutanol, dextrin, dibutyl phthalate, dibutyl sebacate,diethyl phthalate, dimethyl phthalate, glycerin, glycerin monostearate,hypromellose phthalate, mannitol, mineral oil, lanolin alcohols,palmitic acid, polyethylene glycol, polymethacrylate, polyvinyl acetatephthalate, propylene glycol, 2-pyrolidone, sorbitol, stearic acid,triacetin, tributyl citrate, triethanolamine, triethyl citrate, and thelike.

Coatings include, for example, but are not limited to polymethacrylates(pH sensitive) and polyvinyl acetate pthalate (pH sensitive), andhydroxypropyl methylcellulose (moisture barrier), acetyltributylcitrate, acetyltriethyl citrate, calcium carbonate,carboxymethylcellulose sodium, carnauba wax, cellulose acetate,cellulose acetate phthalate, cetyl alcohol, chitosan, ethylcellulose,fructose, gelatin, glycerin, glyceryl behenate, glycerylpalmitostearate, hydroxyethyl cellulose, hydroxyethylmethyl cellulose,hydroxypropyl cellulose, hypromellose, hypromellose phthalate, isomalt,glucose, maltitol, maltodextrin, methylcellulose, microcrystalline wax,paraffin, poloxamer, polydextrose, polyethylene glycol, polyvinylacetate phthalate, polyvinyl alcohol, povidone, shellac, sucrose,titanium oxide, tributyl citrate, triethyl citrate, vanillin, xylitol,zein, talc, triethanolamine, ammonium alginate, chlorpheniraminemaleate, copovidone, ethyl lactate, and the like. When present, coatinglayers may range in thickness from 0.1 to 200 μm thick, such as 1 to 100or 1 to 100 μm. Of interest are coating layers that modulate release ofthe pharmaceutically active agent from the membrane upon contact with atarget physiological site.

Wetting agents include, for example, polyethylene glycol, docusatesodium, sodium lauryl sulfate, polyethylene oxide, lecithin, poloxamer,and povidone, benzalkonium chloride, benzethonium chloride,cethylpyridinium chloride, docusate sodium, hypromellose, poloxamer,polythethylene alkyl ethers, polyoxyethylene alkyl ethers,polyoxyethylene castor oil derivatives, polyoxoethylene sorbitan fattyacid esters, polyoxyethylene stearates, sodium lauryl sulfate, sorbitanesters, benzyl alcohol, benzyl benzoate, cetylpyridinium chloride,cyclodextrins, glycerin monostearate, lecithin, meglumine, poloxomer,povidone, sodium bicarbonate, stearic acid, sulfobutyletherbeta-cyclodextrin, and the like.

The surface of the membrane may also contain an anti-adhesion layer thatprevents an IEM from adhering to the stomach lining or getting blockedby objects in the GI tract such as food residue. An anti-adhesion filmmay also be used to prevent two or more devices from adhering to eachother and blocking each other's communication. In these aspects,materials of interest for use in anti-adhesion layers include, but arenot limited to: ethyl cellulose, microcrystalline cellulose, cellulosederivative, silicates, e.g., magnesium silicates or aluminum silicates,oxides, e.g., titanium oxide, etc. As indicated above, mixtures of theabove materials or materials analogous thereto may be employed.

Of interest in certain aspects are anti-adhesion layers. In theseaspects, materials of interest for use in anti-adhesion layers include,but are not limited to: ethyl cellulose, microcrystalline cellulose,cellulose derivative, silicates, e.g., magnesium silicates or aluminumsilicates, oxides, e.g., titanium oxide, etc. As indicated above,mixtures of the above materials or materials analogous thereto may beemployed.

Membranes may be fabricated using any convenient protocol. Membranefabrication protocols of interest include, but are not limited to, thosedescribed in PCT/US08/77753, the disclosure of which is hereinincorporated by reference.

Vehicle

Ingestible event markers may further include a vehicle component withwhich the IEM and membrane are stably associated. The vehicle componentmay be any convenient physiologically acceptable carrier composition. By“physiologically acceptable carrier composition” is meant a compositionwhich is ingestible, where the composition may be solid or fluid. Solidvehicle configurations of interest include tablet and capsuleconfigurations. The vehicle component, when present, may be fabricatedfrom a variety of different materials. Materials of interest can befound in Remington's Pharmaceutical Sciences, Mace Publishing Company,Philadelphia, Pa., 17th ed. (1985).

As summarized above, ingestible event markers of the invention maycombine one or more IEM/membrane components with a vehicle, where thevehicle may be any convenient physiologically acceptable carriercomponent. In some instances, the vehicle component is configured toimpart a controlled release profile to the pharmaceutically active agentthat is associated with the membrane. For example, the IEM/membranecomponent may be present inside of a solid tablet vehicle, where thesolid tablet breaks down after a certain period of time followingcontact of the IEM with the target physiological site, to allow anyactive agent present in the IEM to be released.

A vehicle may be present even in those aspects where an active agent isnot administered. In some aspects, vehicles are present to enhanceingestibility of an IEM. By stably associating the IEM to a vehicle suchas a tablet or capsule (which may be conventionally sized or smaller),adherence of the IEM to the mouth can be avoided. In some instances thevehicle is a small tablet (i.e., mini-tablet) that is adhered to theingestible event marker, for example with a physiologically acceptableadhesive.

In some instances, IEMs are made up of an IEM stably associated with asolid vehicle component having a tablet configuration. In suchinstances, of interest are tablet vehicle components that are configuredto promote contact of the electrochemical materials or IEMelectrochemical materials with fluid upon contact of the IEM with thetarget physiological site. In such tablet configurations, the tablet mayinclude one or more fluid passageways, such as grooves, channels, tubesor analogous structures, which serve to convey fluid from theenvironment of the IEM to an electrochemical material associated with atablet vehicle. Passageway configurations of interest may also beconfigured to convey any bubbles generated at the electrochemicalmaterial component away from the electrochemical material componentand/or to discourage formation of bubbles at the electrochemicalmaterial component. In such instances, the IEM is configured such thatthe electrochemical material is positioned relative to the passagewaysuch that fluid in the passageway contacts the electrochemical material.An example of such an IEM is shown in FIG. 7. In FIG. 7, IEM 70 includesIEM 71 (made up of IEM circuitry component 72 and membrane 73) stablyassociated with the upper surface of tablet vehicle component 74. Alsoshown are channels 75 and 76 which are configured to provide a fluidpassageway to the underside electrochemical material component of IEMcircuitry component 72. FIG. 7B provides a cross-sectional view of IEM70. In a given tablet configuration, the tablet may include one or morefluid passageways, where multiple fluid passageways may intersect, asdesired to provide for desired movement gas bubbles. FIG. 8 provides anoverhead view of another IEM 80 where tablet vehicle component 81includes fluid passages ways 85, 86, 87 and 88 which intersect beneaththe IEM 83 made up of IEM circuitry component 84 and membrane 82.

In these IEM configurations that include one or more fluid passageways,a given fluid passageway may be empty so as to provide uninhibitedaccess of fluid to the electrochemical material component upon contactof the IEM with a fluid. Alternatively, the fluid passageway may befilled with a material that conveys the fluid from the environment tothe electrochemical material component, such as material that wicksfluid from one location to another, a hydrogel material that absorbsfluid, and the like. Where desired, salts or other agents which controlconductivity may be present.

Pharmaceutically Active Agent

Where desired, the IEM may include a pharmaceutically active agent. Asindicated above, the pharmaceutically active agent, when present, may bepresent in the vehicle and/or membrane. As summarized above, membranesof the invention include an amount of an active agent, such as apharmaceutically active agent or a diagnostic agent.

“Pharmaceutically Active agent” includes any compound or mixture ofcompounds which produces a physiological result, e.g., a beneficial oruseful result, upon contact with a living organism, e.g., a mammal, suchas a human. Pharmaceutically active agents (which may also be referredto herein as “drugs”) are distinguishable from such components asexcipients, carriers, diluents, lubricants, binders and otherformulating aids, and encapsulating or otherwise protective components.The pharmaceutically active agent may be any molecule, as well asbinding portion or fragment thereof, that is capable of modulating abiological process in a living subject. In certain aspects, thepharmaceutically active agent may be a substance used in the diagnosis,treatment, or prevention of a disease or as a component of a medication.In certain aspects, the pharmaceutically active agent may be a chemicalsubstance, such as a narcotic or hallucinogen, which affects the centralnervous system and causes changes in behavior.

The pharmaceutically active agent is capable of interacting with atarget in a living subject. The target may be a number of differenttypes of naturally occurring structures, where targets of interestinclude both intracellular and extracellular targets. Such targets maybe proteins, phospholipids, nucleic acids and the like, where proteinsare of particular interest. Specific proteinaceous targets of interestinclude, without limitation, enzymes, e.g., kinases, phosphatases,reductases, cyclooxygenases, proteases and the like, targets comprisingdomains involved in protein-protein interactions, such as the SH2, SH3,PTB and PDZ domains, structural proteins, e.g., actin, tubulin, etc.,membrane receptors, immunoglobulins, e.g., IgE, cell adhesion receptors,such as integrins, etc., ion channels, transmembrane pumps,transcription factors, signaling proteins, and the like.

The pharmaceutically active agent may include one or more functionalgroups necessary for structural interaction with the target, e.g.,groups necessary for hydrophobic, hydrophilic, electrostatic or evencovalent interactions, depending on the particular drug and its intendedtarget. Where the target is a protein, the pharmaceutically active agentmay include functional groups necessary for structural interaction withproteins, such as hydrogen bonding, hydrophobic-hydrophobicinteractions, electrostatic interactions, etc., and may include at leastan amine, amide, sulfhydryl, carbonyl, hydroxyl or carboxyl group, suchas at least two of the functional chemical groups.

Pharmaceutically active agents of interest may include cyclical carbonor heterocyclic structures and/or aromatic or polyaromatic structuressubstituted with one or more of the above functional groups. Also ofinterest as pharmaceutically active agents are compounds havingstructures found among biomolecules, including peptides, saccharides,fatty acids, steroids, purines, pyrimidines, derivatives, structuralanalogs or combinations thereof. Such compounds may be screened toidentify those of interest, where a variety of different screeningprotocols are known in the art.

The pharmaceutically active agent may be derived from a naturallyoccurring or synthetic compound that may be obtained from a wide varietyof sources, including libraries of synthetic or natural compounds. Forexample, numerous means are available for random and directed synthesisof a wide variety of organic compounds and biomolecules, including thepreparation of randomized oligonucleotides and oligopeptides.Alternatively, libraries of natural compounds in the form of bacterial,fungal, plant and animal extracts are available or readily produced.Additionally, natural or synthetically produced libraries and compoundsare readily modified through conventional chemical, physical andbiochemical means, and may be used to produce combinatorial libraries.Known pharmacological agents may be subjected to directed or randomchemical modifications, such as acylation, alkylation, esterification,amidification, etc. to produce structural analogs.

As such, the pharmaceutically active agent may be obtained from alibrary of naturally occurring or synthetic molecules, including alibrary of compounds produced through combinatorial means, i.e., acompound diversity combinatorial library. When obtained from suchlibraries, the drug moiety employed will have demonstrated somedesirable activity in an appropriate screening assay for the activity.Combinatorial libraries, as well as methods for producing and screeningsuch libraries, are known in the art and described in U.S. Pat. Nos.5,741,713; 5,734,018; 5,731,423; 5,721,099; 5,708,153; 5,698,673;5,688,997; 5,688,696; 5,684,711; 5,641,862; 5,639,603; 5,593,853;5,574,656; 5,571,698; 5,565,324; 5,549,974; 5,545,568; 5,541,061;5,525,735; 5,463,564; 5,440,016; 5,438,119; 5,223,409, the disclosuresof which are herein incorporated by reference.

Broad categories of active agents of interest include, but are notlimited to: cardiovascular agents; pain-relief agents, e.g., analgesics,anesthetics, anti-inflammatory agents, etc.; nerve-acting agents;chemotherapeutic (e.g., anti-neoplastic) agents; neurological agents,e.g., anti-convulsants, etc.

Pharmaceutically active agents of interest include, but are not limitedto: those listed in PCT application serial no. PCT/US2006/016370, thedisclosure of which listed pharmaceutically active agents isincorporated herein by reference.

Salt

Where desired, a given IEM may include a non-active agent saltcomponent, which component is made up of one or more non-active agentsalts.

In some instances, the amount of this salt component present in the IEMis chosen to be sufficient to enhance the strength of the communicationgenerated by the IEM of the IEM when the IEM contacts the targetphysiological site, such as the stomach. The magnitude of communicationstrength enhancement may vary, where in some instances the magnitude ofcommunication strength enhancement is 10X or more, such as 20X or more,including 50X or more, as compared to a suitable control (such as thestrength of a communication generated by an analogous IEM which differsfrom the test IEM of interest solely by lack of the salt component). Theamount of this non-active agent salt component is sufficient to providefor the desired communication strength enhancement. Non-active agentsalts may vary, where non-active agent salts of interest include, butare not limited to: salts of physiologically acceptable electrolytes,such as but not limited to: sodium ion, chloride ion, potassium ion andcalcium ion, magnesium ion, etc. Specific physiologically compatiblesalts of interest include, but are not limited to: KCl, NaCl, MgCl₂, andthe like. When present, this non-active agent salt may be part of one ormore of: the membrane, the IEM and the vehicle.

Anti-Foaming Agent

Also of interest are anti-foaming agents, which agents decrease thesurface tension of gas bubbles. Anti-foaming agents of interest include,but are not limited to: silicone oil-based agents, such as simethicone,sorbitan sesquoleate, etc. When present, the amount of anti-foamingagent present in the IEM may vary, ranging from 0.01 to 10 mg, such as0.1 to 100 μg, and including 0.1 to 10 μg. When present, thisanti-foaming agent may be part of one or more of: the membrane, the IEMand the vehicle.

Surfactants

In some instances, the IEM includes one or more surfactants. Surfactantsof interest include, but are not limited to: ionic surfactants, such asanionic surfactants, cationic surfactants and zwitterionic surfactants,as well as nonionic surfactants and surface active biological modifiers.Surfactants of interest include, but are not limited to: castor oilderivatives, cholesterol, polyglycolyzed glycerides, acetylatedmonoglycerides, sorbitan fatty acid esters, poloxamers, polysorbates,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene compounds,monoglycerides or ethoxylated derivatives thereof, diglycerides orpolyoxyethylene derivatives thereof, sodium docusate, sodiumlaurylsulfate, cholic acid or derivatives thereof, ethoxylated alcohols,ethoxylated esters, ethoxylated amides, polyoxypropylene compounds,propoxylated alcohols, ethoxylated/propoxylated block polymers,propoxylated esters, alkanolamides, amine oxides, fatty acid esters ofpolyhydric alcohols, ethylene glycol esters, diethylene glycol esters,propylene glycol esters, glycerol esters, polyglycerol fatty acidesters, SPAN™ surfactants, such as sorbitan esters), TWEEN™ surfactants,such as sucrose esters, glucose (dextrose) esters, alkali metalsulfates, quaternary ammonium compounds, amidoamines, and aminimides,simethicone, lecithins, alcohols, phospholipids, and mixtures thereof.When present, the surfactant component may be 0.01 to 10%, such as 0.01to 100 ppm, including 0.1 to 100 ppm of the IEM composition. Whenpresent, surfactants may be part of one or more of: the membrane, theIEM and the vehicle.

Disintegrants

In some instances, the IEM compositions include one or moredisintegrants. By disintegrant is meant an agent that enhances break upof at least some portion of the IEM, such as the vehicle or membrane,upon contact with the target physiological site. As such, disintegrantsmay facilitate mechanical disruption of the IEM vehicle component, suchas a tablet, when the IEM contacts a fluid, such as stomach fluid.Disintegrants of interest include, but are not limited to, thosedisintegrants listed above, such as microcrystalline cellulose, starch,sodium starch glycolate, crosslinked polyvinylpyrrolidone, crosslinkedcarboxymethylcellulose, alginic acid, etc. When present, thedisintegrant component may range from about 0.01 to 15%, such as 0.01 to100 ppm, including 0.1 to 10 ppm of the IEM composition. When present,disintegrants may be part of one or more of: the membrane, the IEM andthe vehicle.

Antioxidants

The IEM compositions may also include one or more antioxidants whichserve to enhance shelf-life stability of the IEM. Antioxidants ofinterest include, but are not limited to: tocopherol and derivatives,ascorbic acid and derivatives, butylated hydroxyanisole, butylatedhydroxytoluene, fumaric acid, malic acid, propyl gallate, metabisulfatesand derivatives. When present, antioxidants may range from 0.01 to 10%,such as 0.01 to 100 ppm and including 0.1 to 1 ppm. When present,anti-oxidants may be part of one or more of: the membrane, the IEM andthe vehicle.

Preservatives

IEMs of the invention may further include preservatives such as, but notlimited to, benzalkonium chloride and derivatives, benzoic acid, benzylalcohol and derivatives, bronopol, parabens, centrimide, chlorhexidine,cresol and derivatives, imidurea, phenol, phenoxyethanol, phenylethylalcohol, phenylmercuric salts, thimerosal, sorbic acid and derivatives.The preservative may be present from in amounts ranging from 0.01 to 10mg, such as 0.1 to 100 μg and including 0.1 to 1 μg. When present,preservatives may be part of one or more of: the membrane, the IEM andthe vehicle.

Micro-Environment Modification Agents

IEMs of the invention may include one or more micro-environmentmodification agents that modify or control the micro-environment of anIEM upon contact with a target physiological site. Micro-environmentmodification agents of interest include but are not limited tosurfactants, distintegrants, anti-oxidants, and preservatives. A givenIEM may include one or more of these components as a micro-environmentmodification agent. Examples and amounts of each of these types ofagents that may be present are provided above. When present,micro-environment modification agents may be part of one or more of: themembrane, the IEM and the vehicle.

Balanced Soluble/Insoluble Components

In some instances, IEM compositions of the invention are those in whichthe water insoluble and water soluble components of the vehicle arepresent in a ratio that is selected to provide for desiredcharacteristics, such as dissolution of the vehicle, operations of theIEM, and the like. In some instances, the fraction of water insolublecomponents in the vehicle may range from 0.01 to 1, such as 0.1 to 0.9and including 0.5 to 0.8. In some instances, the ingestible event markerhas a fraction of soluble components up to 90% by weight.

Absorbent Component

An ingestible event marker may include a component that absorbs fluid,e.g., water, in order to increase the weight of the IEM (for example toensure that the IEM sinks when it contacts fluid at a physiologicalsite). This absorbent component may be the membrane, vehicle, or somedistinct component of the IEM, such as an overlayer or coating, asdesired. When present, this absorbent component may be fabricated from avariety of suitable materials, such as the hydrogel materials listedabove.

Controlled Activation Element

IEMs of the invention may include a controlled activation element. Thecontrolled activation element of the IEM that provides for controlledactivation may be responsive to a variety of different types of stimuli.Stimuli of interest for which the controlled activation element can beconfigured to be responsive to include but are not limited to: liquid(wetting), time, pH, ionic strength, conductivity, biological molecules(e.g. specific proteins or enzymes that are present in the stomach,small intestine, colon), blood, temperature, specific auxiliary agents(foods ingredients such as fat, salt, or sugar, or other pharmaceuticalswhose co-presence is clinically relevant), bacteria in the stomach,pressure, and light.

The controlled activation element is made up of one or more componentsthat provides for the desired controlled activation functionality, suchthat the controlled activation element is responsive to the stimulus ofinterest. The nature of the component or components that make up thecontrolled activation element may vary. For example, where the stimulusof interest is temperature, the controlled activation element may be abarrier of a material, such as a film (e.g., a polymeric film) whosesolubility is a function of temperature, specifically one that becomessoluble at or near body temperature. Such a film may beinsoluble/impermeable to water at room temperature but soluble/permeableat 37° C. Materials of interest that may be used for such films include,but are not limited to the polymeric materials listed below. In thoseaspects where pressure is the stimuli of interest, the controlledactivation element may be a pressure sensitive material, e.g., a capsuleor shell (for example, made of a cellulosic material), that has aspecific mechanical strength such that at a pressure threshold above thethreshold the element will be crushed and allow the higly reliable eventmarker to be activated and communicate. In other aspects of interest,the stimulus may be light. For example, the stimulus may be afluorescent label which has been attached to a tumor. As the IEM passesby the tumor, the controlled activation element may include a componentthat provides light at a stimulating wavelength for the label and also acomponent that detects emitted light from the label. Any convenientlight source and detector may be employed. When the detector componentdetects the emitted light, it will activate the IEM in a controlledactivation manner.

In certain aspects, the one or more controlled activation components ofthe invention provide for controlled activation, i.e., activation in amanner that is substantially, if not completely, independent of targetsite environment, as reviewed above. In one aspect of interest, thecontrolled activation component includes a dried conductive medium that,upon combination with target site fluid, produces an ionic medium in thepresence of the first and second dissimilar materials to activate thebattery, e.g., as reviewed above. When present, the dried conductivemedium precursor may be any of a variety of different types ofcompositions. Compositions of interest include, but are not limited to:salts of physiologically acceptable electrolytes, such as but notlimited to: sodium ion, chloride ion, potassium ion and calcium ion,magnesium ion, etc. Specific physiologically compatible salts ofinterest include, but are not limited to: KCl, NaCl, MgCl₂, and thelike. Aspects of the invention include the presence of a driedconductive medium precursor. When the precursor is a salt, e.g., asdescribed above, the dried salt may be provided in any convenientformat, such as a lyophilized salt composition.

Controlled activation elements of interest are further described in PCTapplication serial no. PCT/US2007/082563 published as WO 2008/052136;the disclosure of which is herein incorporated by reference.

IEM Manufacture

A variety of manufacturing protocols may be employed to produce IEMs ofthe invention. Where the IEM does not include a vehicle, the IEM andmembrane components may be produced as described above. Where the IEMfurther includes a vehicle, the IEM may be stably associated with thevehicle in some manner. By stably associated is meant that the IEM andthe vehicle do not separate from each other, at least until administeredto the subject in need thereof, e.g., by ingestion. The IEM may bestably associated with the vehicle in a number of different ways.

IEM fabrication protocols of interest include, but are not limited to,those described in PCT application serial nos. PCT/US2006/016370 andPCT/US08/77753; as well as in U.S. Provisional Application Ser. No.61/142,849; the disclosures of which are herein incorporated byreference.

Systems

Also provided are systems that include an IEM and a communicationdetection component, e.g., in the form of a receiver, sometimes referredto herein as a “detector”. Receivers of interest are those that areconfigured to receive a signal from an IEM. The detection component mayvary significantly depending on the nature of the communication that isgenerated by the IEM. As such, the receiver may be configured to receivea variety of different types of communications, including but notlimited to: RF signals, magnetic signals, conductive (near field)signals, acoustic signals, etc. In certain aspects, the receiver isconfigured to receive a signal conductively from an IEM, such that thetwo components use the body of the patient as a communication medium. Assuch, the signal that is transferred between the IEM and the receivertravels through the body, and requires the body as the conductionmedium. The IEM emitted signal may be transmitted through and receivedfrom the skin and other body tissues of the subject body in the form ofelectrical alternating current (a.c.) voltage signals that are conductedthrough the body tissues. As a result, such aspects do not require anyadditional cable or hard wire connection, or even a radio linkconnection for transmitting the sensor data from the autonomous sensorunits to the central transmitting and receiving unit and othercomponents of the system, since the sensor data are directly exchangedvia the skin and other body tissues of the subject. This communicationprotocol has the advantage that the receivers may be adaptably arrangedat any desired location on the body of the subject, whereby thereceivers are automatically connected to the required electricalconductor for achieving the communication, i.e., the communication iscarried out through the electrical conductor provided by the skin andother body tissues of the subject.

The receiver may include a variety of different types of receiverelements, where the nature of the receiver element necessarily variesdepending on the nature of the signal produced by the signal generationelement. In certain aspects, the receiver may include one or moreelectrochemical materials (such as 2 or more electrochemical materials,3 or more electrochemical materials, and/or includes multiple pairs ofelectrochemical materials, such as 2 or more, 3 or more, 4 or more pairsof electrochemical materials, etc., for detecting signal emitted by anIEM. In certain aspects, the receiver includes two or threeelectrochemical materials that are dispersed at a distance from eachother, e.g., a distance that allows the electrochemical materials todetect a differential voltage. The distance between any twoelectrochemical materials may vary, and in certain aspects ranges fromabout 0.1 to about 5 cm, such as from about 0.5 to about 2.5 cm, e.g.,about 1 cm.

In addition to receiving elements, such as electrodes electrochemicalmaterials, receivers of the invention may include one or more integratedcircuit components, one or more power components (such as powerreceivers or batteries), signal transmission components, housingcomponents, etc.

The receivers of interest include both external and implantablereceivers. In external aspects, the receiver is ex vivo, by which ismeant that the receiver is present outside of the body during use. Wherethe receiver is implanted, the receiver is in vivo. The receiver isconfigured to be stably associated with the body, e.g., either in vivoor ex vivo, at least during the time that it receives the emitted signalfrom the IEM.

In certain aspects, the receiver is configured to provide data of areceived signal to a location external to said subject. For example, thereceiver may be configured to provide data to an external data receiver,e.g., which may be in the form of a monitor (such as a bedside monitor),a computer, a personal digital assistant (PDA), phone, messaging device,smart phone, etc. The receiver may be configured to retransmit data of areceived signal to the location external to said subject. Alternatively,the receiver may be configured to be interrogated by an externalinterrogation device to provide data of a received signal to an externallocation.

Receivers of interest include, but are not limited to, those receiversdisclosed in: PCT application serial nos. PCT/US2006/016370 published asWO 2006/116718; PCT/US2008/52845 published as WO 2008/095183;PCT/US2007/024225 published as WO 2008/063626 and PCT/US2008/085048; aswell as U.S. Provisional Application Ser. No. 61/160,289; thedisclosures of which applications (and particularly receiver componentsthereof) are herein incorporated by reference.

Systems of the invention may include an external device which isdistinct from the receiver (which may be implanted or topically appliedin certain aspects), where this external device provides a number offunctionalities. Such an apparatus can include the capacity to providefeedback and appropriate clinical regulation to the patient. Such adevice can take any of a number of forms. By example, the device can beconfigured to sit on the bed next to the patient, e.g., a bedsidemonitor. Other formats include, but are not limited to, PDAs, phones,such as smart phones, computers, etc. In some instances, the externaldevice is configured to provide pharmacologic and physiologicinformation in a form that can be transmitted through a transmissionmedium, such as a telephone line, to a remote location such as aclinician or to a central monitoring agency. The external device canread out the information described in more detail in other sections ofthe subject patent application, both from pharmaceutical ingestionreporting and from physiological sensing devices, such as is producedinternally by a pacemaker device or a dedicated implant for detection ofthe pill. The purpose of the external apparatus is to get the data outof the patient and into an external device. One feature of the externalapparatus is its ability to provide pharmacologic and physiologicinformation in a form that can be transmitted through a transmissionmedium, such as a telephone line, to a remote location such as aclinician or to a central monitoring agency.

Methods

Aspects of the invention further include methods of using IEMs, such asthose described above. Methods of the invention generally includeadministering an IEM to a subject, e.g., by self-administration or viathe assistance of another, such as a health care practitioner.Generally, methods of the invention will include placing the IEM in themouth of a subject such that the subject swallows the IEM. In thismanner, the subject ingests the IEM. IEMs may be employed with a varietyof subjects. Generally such subjects are “mammals” or “mammalian,” wherethese terms are used broadly to describe organisms which are within theclass mammalia, including the orders carnivore (e.g., dogs and cats),rodentia (e.g., mice, guinea pigs, and rats), and primates (e.g.,humans, chimpanzees, and monkeys). In certain aspects, the subjects willbe humans.

Following ingestion, the methods include emitting one or more signalsfrom the ingested IEM, for example when the IEM contacts the targetphysiological site. As reviewed above, the nature of the emitted signalmay vary greatly. In some instances, the emitted signal is aconductively transmitted signal. Methods of the invention may alsoinclude receiving a signal emitted from an IEM, e.g., at a receiver,such as described above. In some instances, the received signal is aconductively transmitted signal.

IEMs may be employed in a variety of different applications, whichapplications may be both medical and non-medical in nature. Applicationsof interest include, but are not limited to: monitoring patientcompliance with prescribed therapeutic regimens; tailoring therapeuticregimens based on patient compliance; monitoring patient compliance inclinical trials; monitoring usage of controlled substances; monitoringthe occurrence of a personal event of interest, such as the onset ofsymptoms, etc., and the like. Applications of interest are furtherdescribed in PCT application serial no. PCT/US2006/016370 published asWO/2006/116718; PCT application serial no. PCT/US2007/082563 publishedas WO/2008/052136; PCT application serial no. PCT/US2007/024225published as WO/2008/063626; PCT application serial no.PCT/US2007/022257 published as WO/2008/066617; PCT application serialno. PCT/US2008/052845 published as WO/2008/095183; PCT applicationserial no. PCT/US2008/053999 published as WO/2008/101107; PCTapplication serial no. PCT/US2008/056296 published as WO/2008/112577;PCT application serial no. PCT/US2008/056299 published asWO/2008/112578; and PCT application serial no. PCT/US2008/077753; thedisclosures of which are herein incorporated by reference.

Kits

Also provided are kits that include one or more IEMs, such as describedabove. In those aspects having a plurality of IEMs, the IEMs may bepackaged in a single container, e.g., a single tube, bottle, vial, andthe like, or one or more dosage amounts may be individually packagedsuch that certain kits may have more than one container of IEMs. Incertain aspects the kits may also include a receiver, such as reviewedabove. In certain aspects, the kits may also include an external monitordevice, e.g., as described above, which may provide for communicationwith a remote location, e.g., a doctor's office, a central facilityetc., which obtains and processes data obtained about the usage of thecomposition.

The subject kits may also include instructions for how to practice thesubject methods using the components of the kit. The instructions may berecorded on a suitable recording medium or substrate. For example, theinstructions may be printed on a substrate, such as paper or plastic,etc. As such, the instructions may be present in the kits as a packageinsert, in the labeling of the container of the kit or componentsthereof (i.e., associated with the packaging or sub-packaging) etc. Inother aspects, the instructions are present as an electronic storagedata file present on a suitable computer readable storage medium, e.g.CD-ROM, diskette, etc. In yet other aspects, the actual instructions arenot present in the kit, but means for obtaining the instructions from aremote source, e.g. via the internet, are provided. An example of thisaspect is a kit that includes a web address where the instructions canbe viewed and/or from which the instructions can be downloaded. As withthe instructions, this means for obtaining the instructions is recordedon a suitable substrate. Some or all components of the subject kits maybe packaged in suitable packaging to maintain sterility. In many aspectsof the subject kits, the components of the kit are packaged in a kitcontainment element to make a single, easily handled unit, where the kitcontainment element, e.g., box or analogous structure, may or may not bean airtight container, e.g., to further preserve the sterility of someor all of the components of the kit.

It is to be understood that this invention is not limited to particularaspects described, as such may vary. It is also to be understood thatthe terminology used herein is for the purpose of describing particularaspects only, and is not intended to be limiting, since the scope of thepresent invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, representativeillustrative methods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual aspects described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalaspects without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and aspects of the invention as well as specificexamples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryaspects shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

What is claimed is:
 1. A highly reliable event marker comprising: asupport; a control circuit physically associated with the support tocontrol the highly reliable event marker; a first electrochemicalmaterial physically associated with the support and electrically coupledto the control circuit; a second electrochemical material electricallycoupled to the control circuit and physically associated with thesupport at a location different from the location of the first material,such that the first and second electrochemical materials areelectrically isolated from each other; and a membrane physicallyassociated to the support and positioned relative to the firstelectrochemical and second electrochemical materials to generate avirtual dipole length larger than an actual dipole length defined by thefirst and the second electrochemical materials.
 2. The highly reliableevent marker of claim 1 wherein the control circuit controls the voltagebetween the first material and the second electrochemical materials. 3.The highly reliable ingestible event marker according to claim 1 whereinthe first and the second electrochemical materials are selected toprovide a voltage potential difference when in contact with a conductingliquid at a target physiological site, wherein the potential differenceprovides power for communication.
 4. The highly reliable ingestibleevent marker according to claim 1 wherein the membrane is a planarstructure having an outer edge that extends beyond the edge of the firstand second electrochemical materials.
 5. The highly reliable ingestibleevent marker according to claim 1 wherein the membrane comprises atleast one of multiple coatings and multiple layers
 6. The highlyreliable ingestible event marker of claim 1 further comprising at leastone controlled activation element.
 7. The highly reliable ingestibleevent marker of claim 1 further comprising at least one of a non-activeagent salt, an anti-foaming agent, a micro-environment modificationagent and a soluble component having a weight equal or greater to 90% ofthe overall weight of the highly reliable event marker.
 8. The highlyreliable ingestible event marker according to claim 1 wherein themembrane has at least one of opposing curved edges, one or moreprojections, or one or more deployable elements.
 9. The highly reliableingestible event marker of claim 1 further comprising a weightnon-centrically associated with the membrane.
 10. The highly reliableingestible event marker of claim 1 further comprising adding awater-swellable component non-centrically associated with the membrane.11. The highly reliable ingestible event marker according to claim 1,wherein the highly reliable event marker is physically associated withan active agent.
 12. The highly reliable ingestible event markeraccording to Claim1 1, wherein the active agent is physically associatedwith the membrane.
 13. The highly reliable ingestible event markeraccording to claim 11, wherein the membrane releases the active agent ina phased manner.
 14. The highly reliable ingestible event markeraccording to claim 11, wherein the active agent comprises at least onefluid passageway.
 15. A system comprising: a highly reliable ingestibleevent marker comprising: a support; a control circuit physicallyassociated with the support to control the highly reliable event marker;a first electrochemical material physically associated with the supportand electrically coupled to the control circuit; a secondelectrochemical material electrically coupled to the control circuit andphysically associated with the support at a location different from thelocation of the first material, such that the first and secondelectrochemical materials are electrically isolated from each other; anda membrane physically associated to the support and positioned relativeto the first electrochemical and second electrochemical materials togenerate a virtual dipole length larger than an actual dipole lengthdefined by the first and the second electrochemical materials.
 16. Thesystem of claim 15 wherein the highly reliable ingestible event markeris associated with an active agent.
 17. The system of claim 15 whereinthe active agent is physically associated with the membrane.
 18. Thesystem of claim 15 wherein the highly reliable event marker furthercomprising at least one of a non-active agent salt, an anti-foamingagent, a micro-environment modification agent and a soluble componenthaving a weight equal or greater to 90% of the overall weight of thehighly reliable event marker.
 19. The system of claim 15 wherein themembrane is a planar structure having an outer edge that extends beyondthe edge of the first and second electrochemical materials.
 20. Thesystem of claim 15 wherein the membrane has at least one of opposingcurved edges, one or more projections, or one or more deployableelements.